This invention relates to methods, devices and test kits for use in monitoring the ovulation cycle in female mammals, especially humans.
The invention is particularly, although not solely, concerned with the provision of reliable information concerning fertility status as an aid to contraception by the use of simple practical procedures that can readily be applied by unskilled persons, e.g. in the home.
Throughout this specification, the expression xe2x80x9cfertile phasexe2x80x9d is used to mean that interval in a female menstrual cycle, spanning the event of ovulation, during which it is most likely that intercourse will result in fertilization, because of the normal viability of spermatozoa and ova.
There is a wealth of scientific literature on the urinary hormone profiles during the ovulation cycle. The relative usefulness of estradiol derivatives, especially estrone-3-glucuronide (E3G), lutenising hormone (LH), and progesterone derivatives, especially pregnanediol-3-glucuronide (P3G), as indicators of the status of the cycle, has been studied extensively.
Procedures are already available commercially to enable LH to be used to enhance the likelihood of conception.
The article xe2x80x9cA prospective multicentre study to develop universal tests for predicting the female phase in womenxe2x80x9d (WHO, Int J Fertil 30(3) 1985 p 18-30) discusses the prediction of the fertile phase in an ovulation cycle by measuring the daily levels of the hormones E3G and Pd-3-G (ie. P3G) in early morning urine. Although the primary purpose of this study is to analyse for differences in fertile phase calculation in different races of women, this paper does suggest that the relative levels of E3G and Pd-3-G may be used in predicting the start and end of the fertile phase. If the start of the fertile phase is defined by the sustained rise in the level of urinary E3G, then the end of that fertile phase (ie the start of the luteal phase) may be assumed to be 5 days after the E3G peak is observed. Similarly, if the start of the fertile phase is taken to be an increase in the E3G: Pd-3-G ratio, the end is defined as being 6 days after the peak value of this index is observed.
The article xe2x80x9cNew assays for identifying the fertile periodxe2x80x9d by Brown, Blackwell, Holmes and Smyth (Int J Gynecol Obstet 1989 Suppl 1 p111-122) discusses the use of estrogen level measurements as an ovulation predictor, although estrogen on its own is stated as being an unreliable ovulation predictor. Pregnanediol is also suggested as a hormone marker to signify the end of the fertile phase. In the studies referred to in this paper, the average number of days of abstinence from intercourse per menstrual cycle was seventeen; furthermore, the user satisfaction with this method of contraception, and the willingness of test couples to continue using it, was found to be inversely related to length of the abstinence phase. Daily hormone measurements were made, although the article does speculate that, when the fertile phase is predicted by E3G and P3G measurements, that 12 tests per month may be sufficient. In an effort to get the abstinence period down to the quoted xe2x80x9ctheoreticalxe2x80x9d minimum of seven days, it is suggested that it may be possible to use a method of fertile phase prediction using a combination of cervical mucus symptoms and non-symptomatic markers.
The article xe2x80x9cBiochemical Indices of Potential Fertilityxe2x80x9d by Collins (Int J Gynecol Obstet, 1989, Suppl. 35-43) discusses the possible use of multiple analytes in urine to delineate the fertile phase. However, the tests carried out had a success rate in predicting the fertile phase of around 80% or less; also, the fertile period predicted (and hence the abstinence period) was in all cases more than 10 days.
EP 367 615 (Monoclonal Antibodies Inc) provides a method of natural birth control in which the level of a urinary metabolite (progesterone) is measured as an indicator or the stage reached in the menstrual cycle. However, the only hormones suggested are progesterone metabolites, and hence the method can only be an indicator of the luteal phase safe period.
The article xe2x80x9cFertility Awareness: Jet-Age Rhythm Method?xe2x80x9d by Djerassi (Science, June 1, 1990, p 1061-2) suggests the prediction of the fertile phase for contraceptive, and in particular conception purposes by the analysis of body fluids (eg blood, urine or saliva). In this article, it is suggested that the start of the fertile phase could be predicted safely by detecting the rise in estradiol (or its metabolites). The start of the luteal phase could be predicted by either a second increase in estradiol concentration, or a major increase in progesterone (or its metabolites).
The clear inferences to be drawn from this literature are:
estradiol and its metabolites, especially E3G, are the only urinary hormones that can be used to provide sufficiently early warning, during the pre-ovulation phase of the cycle, for contraceptive purposes; and
any successful fertility awareness test which aims to provide adequate contraceptive information, must involve measurement of E3G or an equivalent molecule, and must identify the rise in E3G concentration that precedes ovulation.
Nevertheless, the literature (for example, Djerassi) also indicates that no satisfactory test based on E3G has yet been developed.
It is generally accepted that the background level of urinary E3G fluctuates so widely from individual to individual that no simple, universally applicable assay can be devised.
To try to overcome this problem, complicated mathematical procedures, eg. xe2x80x9cCUSUMxe2x80x9d, have been evolved to calculate a threshold E3G concentration during a current ovulation cycle, and to identify any significant rise above the calculated threshold. Such systems have the disadvantage that by the time the mathematics has recognised that a significant rise is taking place, it may already be xe2x80x9ctoo latexe2x80x9d if the objective is contraception. Accordingly it is generally accepted that the CUSUM approach cannot provided prospective information about fertility status. A review of CUSUM-based methods is found in Royston: Statistics in Medicine, Vol. 10 (1991) 221-240.
Overall, from this general survey of the prior art, it can be seen that in previously known techniques of fertile period prediction, the period predicted is unduly long, giving rise to an unduly long period of abstinence. Very often, such as for example shown in EP 367 615, the long period of abstinence extends from menstruation to the end of the fertile period. This, in part, is due to the difficulty in pinpointing the start of the fertile period. It has also been a feature of prior art methods that frequent, often daily, measurements of urinary hormone levels throughout the current cycle have been necessary for the method to be deemed reliable as a method of contraception.
For the purposes of this specification, estradiol and all measurable estradiol metabolites, will collectively be referred to henceforth as xe2x80x9cE3Gxe2x80x9d. In addition to estrone-3-glucuronide already mentioned, estradiol metabolites that can also be assayed for the purposes of the invention include estradiol-3-glucuronide, estradiol-17-glucuronide, estriol-3-glucuronide, estriol-16-glucuronide and (principally for non-human subjects) estrone-3-sulphate. As will be appreciated from the following description, the invention can readily be applied to data derived from the measurement of body fluid concentrations of other analytes of significance in relation to the status of the ovulation cycle. Generally, the most suitable analytes are hormones and their metabolites. Follicle stimulating hormone (FSH) is an example. Examples of alternative body fluids, which are relatively accessible, are saliva, crevicular fluid, sweat, sebum, tears and vaginal fluid. In principle internal fluids, such as blood, can be used but are generally not preferred because they can only be accessed readily by invasive techniques.
The skilled reader will also appreciate that the body fluid xe2x80x9cconcentrationxe2x80x9d of the chosen analyte or analytes need not be measured in absolute terms, although this can of course be done if desired. Generally, it will be sufficient to assay an analyte in a manner which yields a signal, convertible to numerical data, related to the actual concentration, so that such data can be compared with similar data obtained at a different stage in the cycle to determine whether or not a significant change in actual concentration has occurred. Accordingly, where the specification and claims below refer to the xe2x80x9cconcentrationxe2x80x9d of an analyte, this expression should be interpreted broadly.
The invention provides a method of monitoring the status of a current ovulation cycle of an individual mammalian, eg human female subject, involving testing of the body fluid concentration of an analyte of significance in relation to the status of the ovulation cycle during at least part of the pre-ovulation phase of the current ovulation cycle of the individual subject, and identification from the results of such testing an analyte concentration change indicative of imminent ovulation, relative to an analyte concentration reference value that has been adapted to the individual human subject on the basis of analyte concentration test data obtained from the individual subject during one or more previous ovulation cycles.
The analyte concentration may be measured in absolute terms, or in relative terms e.g. as a ratio relative to the concentration of a reference analyte present in the same sample of body fluid.
More generally, the invention includes any comparable method in which a body fluid characteristic (e.g. viscosity, ionic strength, or conductivity) of significance in relation to the status of the ovulation cycle, is compared to a reference value that is adapted to an individual subject on the basis of test data obtained from the individual subject during one or more previous ovulation cycles.
Preferably, the method relies solely on the results of urine tests.
Preferably, the method does not involve the measurement of basal body temperature, especially as such measurement generally needs to be conducted throughout each cycle.
Preferably, the analyte is estradiol or a metabolite thereof, such as estrone-3-glucuronide.
A further embodiment of the invention is electronic means for use in a method of monitoring the status of a current mammalian, eg human, ovulation cycle, programmed to process analyte concentration test data obtained from testing of a body fluid conducted during at least part of the pre-ovulation phase of the current cycle, and to identify via said processing an analyte concentration change indicative of imminent ovulation, relative to an analyte concentration reference value that is adapted to an individual subject on the basis of analyte concentration test data obtained from the individual subject during one or more previous ovulation cycles.
Preferably, the electronic means is incorporated in a recording device having means to record the results of analyte concentration tests, and means to display information concerning the status of the current ovulation cycle of an individual subject whose analyte concentration has been tested. Preferably, the recording device has means to measure the result of an analyte concentration test conducted using a testing device presented to the recording device.
The invention includes a body fluid analyte concentration testing device when used in conjunction with an electronic means and recording device combination of the invention, which testing device comprises a body fluid sample collecting means and an immunochromatographic testing means which provides the test result in a form readable by the test result measuring means of the recording device.
Another aspect of the invention is a test kit for providing awareness of the status of a current mammalian, human, ovulation cycle, comprising one or more testing devices for determining the concentration (in relative or absolute terms) in a body fluid of an analyte of significance in relation to the status of the ovulation cycle, together with electronic means programmed to process analyte concentration test data obtained during at least part of the pre-ovulation phase of the current cycle and to identify therefrom an analyte concentration change indicative of imminent ovulation, relative to an analyte concentration reference value that is adapted to an individual subject on the basis of analyte concentration test data obtained from the individual subject during one or more previous ovulation cycles.
Preferably the test kit comprises a plurality of disposable body fluid testing devices.
In a particularly preferred test kit of the invention, wherein the principal analyte is estradiol or a metabolite thereof, such as E3G, usually measured in urine, the testing devices additionally test the urinary LH concentration of the individual subject, and the LH concentration test results so obtained are used by the electronic means in conjunction with the other analyte concentration test results.
An important aspect of the invention is a method of predicting the fertile period during a current ovulation cycle of an individual mammalian, eg human, subject by detecting, in the pre-ovulation phase, a body fluid concentration change of an analyte of significance in relation to the status of the ovulation cycle, wherein the concentration change is determined by reference to a threshold concentration determined for the individual subject from measurements of the analyte concentration in the body fluid during the pre-ovulation phase of at least one previous ovulation cycle. Preferably the analyte is urinary E3G, in which event the urinary E3G threshold concentration adopted for the current cycle is preferably the concentration that is, in a previous ovulation cycle, exceeded more frequently during the total number of days constituting the transition phase of that previous cycle than during the same number of days in the infertile phase immediately preceding said transition phase.
The invention includes a device for monitoring the mammalian, eg human, ovulation cycle, comprising means for initiating the recording of a cycle, means for measuring (if necessary in conjunction with one or more testing devices readable by the monitoring device) and recording urinary E3G concentration, means for determining a threshold urinary E3G concentration from measurements taken during the infertile and transition phases of at least one preceding cycle, and means for alerting a user if a measured urinary E3G concentration during the pre-fertile phase of a current cycle exceeds the determined threshold. The invention also includes a kit for monitoring the mammalian, eg human, ovulation cycle, comprising such a device together with at least one testing device capable of being used to measure urinary E3G concentration.
A further aspect of the invention is an electronic means, such as a microprocessor, programmed for use in accordance with a method of the invention.
Nowhere in the literature is there any suggestion that the analyte concentration reference value, e.g. threshold level, should be calculated on the basis not of measurements taken during the current cycle, but instead from one or more previous cycles in the same individual.
According to a preferred embodiment of the invention, for the purpose of determining the threshold applicable to an individual subject, it is convenient to sub-divide the portion of the ovulation cycle during which E3G level is relevant, into a number of distinct phases as follows:
i) The fertile phase, which can be regarded as the phase spanning days xe2x80x9cxe2x88x923xe2x80x9d to xe2x80x9c+2xe2x80x9d inclusive relative to the day of actual ovulation. Ovulation day can be accurately pinpointed by measurement of urinary LH levels, for example, taking ovulation to occur on the day following LH maximum urinary concentration.
ii) The transition phase, during which warning of ovulation is required if the monitoring method is to provide a safe basis for contraceptive purposes. The transition phase can be regarded as the phase spanning days xe2x80x9cxe2x88x928xe2x80x9d to xe2x80x9cxe2x88x924xe2x80x9d inclusive relative to the day of actual ovulation.
iii) The infertile phase, which can be regarded as the phase from the onset of menses up to and including day xe2x80x9cxe2x88x929xe2x80x9d relative to the day of actual ovulation.
The threshold level of urinary E3G should be determined from measurements of E3G concentration during the transition and pre-fertile phases of one or more previous cycles. While the threshold for the individual subject is being established, regular (preferably daily) measurements of urinary E3G concentration should be taken during these phases over at least one cycle and more preferably over at least two cycles, and ideally over at least three cycles. When more than one establishing cycle is used, these are preferably consecutive.
Actual ovulation can be determined, if desired, at the same time by methods already known per se, such as the detection of LH surge, P3G rise, or other bodily changes such as elevated basal body temperature (BBT). LH surge detection is most preferred for this purpose. The expression xe2x80x9cLH surgexe2x80x9d is used herein to mean the dramatic rise in LH concentration that precedes the event of ovulation. In the art, reference is made also to xe2x80x9cLH maxxe2x80x9d, i.e. the peak concentration of LH. In the majority of individuals, these are for all practical purposes simultaneous, when the cycle is monitored on a day-by-day basis. However, in a few individuals, perhaps 20% of the population, the actual peak concentration of LH is not observed until the day following the main concentration rise. For the purposes of the invention, we prefer to use the observable rise as the critical parameter.
After an appropriate E3G threshold has been established, regular E3G testing can be discontinued during the early part of the infertile phase of the current cycle. Instead, testing can be commenced at a set time after the onset of menses, for example.
If the method is to be used for contraceptive purposes, the user should be warned that the subject is at least likely to be fertile from the time an elevated level of E3G is detected.
For practical purposes, the threshold can be defined as the E3G concentration which is exceeded more frequently during the transition phase than during the infertile phase. For example, it may be exceeded on not more than 30% of the days in the infertile phase, but exceeded on not fewer than 60% of the days in the transition phase. More preferably the threshold is the E3G concentration which is exceeded on not more than 20% of the days in the infertile phase, but which is exceeded on not fewer than 80% of the days in the transition phase.
It will be found that the E3G threshold will vary widely from one individual subject to another, but generally will be in the range of about 5 to about 40 ng/ml. For many women, the threshold above which an elevated E3G level is recorded is about 30 ng/ml.
Although, if desired, a precise threshold could be derived for each individual subject, it is more convenient to simplify the method by using a range of xe2x80x9cthreshold bandsxe2x80x9d eg. 5, 10, 15, 20, 30, 40 and 50 ng/ml thresholds, and assigning a particular threshold band to each individual subject based on the E3G information derived in preceding cycles. We have found that the adoption of threshold bands is sufficiently accurate to enable reliable contraceptive advice to be obtained. The assays used in the method can be formulated to recognise when such bands have been exceeded.
In an article by Brown et al, Int. J. Gynecol. Obstet. 1989 Suppl. 1, pages 111-122, entitled xe2x80x9cNew assays for identifying the fertile periodxe2x80x9d, a method is described in which urinary estrogen is measured, and the statement is made that:
xe2x80x9c. . . the daily increment in estradiol production during the rise to the pre-ovulatory peak is remarkably constant for all cycles, being very close to a factor of 1.4 per day.xe2x80x9d
As a population statistic, this quoted value of 1.4 for the daily increment during the pre-ovulatory rise may be correct, but in practice this factor varies very considerably from one individual to another. In an incremental or ratiometric method of deriving data from successive concentration assays of estradiol or a metabolite thereof (such as urinary E3G), it is unwise to rely on an increment of 1.4 as being a universal trigger significant of the pre-ovulatory rise. In practice we have found that the necessary trigger can be an incremental factor as high as 2.0, in which event a factor of 1.4 would not be significant in relation to the typical background fluctuations in E3G concentration in the individual concerned. In other individuals we have found that the necessary trigger is significantly lower than 1.4, and if a factor of 1.4 is chosen the pre-ovulatory E3G concentration rise would not be detected.
Accordingly, the present invention can be applied usefully in any method of monitoring the ovulation cycle which involves incremental (xe2x80x9cratiometricxe2x80x9d) analysis of a detectable variable parameter of significance during the pre-ovulatory phase of the cycle and wherein a warning of imminent ovulation is given when a pre-determined reference ratio is identified, the reference ratio having been determined for the individual subject based on data derived from one or more previous ovulation cycles in the same individual subject. The expression xe2x80x9canalyte concentration reference valuexe2x80x9d as used herein includes reference values in ratio form.
The present invention can therefore be applied to advantage in any of the proposed assay systems which involve mathematical analysis of successive analyte concentrations, particularly urinary E3G concentrations by, for example, xe2x80x9cCUSUMxe2x80x9d analysis. Usually, the successive analyte concentrations (or indeed, successive measurements of any relevant parameter in accordance with the invention) are recorded on succcessive days.
Conveniently, the first assay of a current cycle is made at least 5 days after the commencement of menstruation.
Once an elevated E3G level, i.e. above a predetermined threshold, has been detected, although it cannot be said for certain that the woman has entered the fertile period of her cycle, it can be said with reasonable certainly that the ovulation day of her cycle is imminent.
An advantage of the method is that it can work by single event trigger, e.g. the observation of an elevated level of one hormone.
The following description is provided in relation to the particular urinary hormones E3G, LH, and P3G, although it will be readily appreciated that the principles of the method can be used in relation to other biochemical markers, for example the hormones estradiol and progesterone, found for example in the blood or in saliva. The method of the invention may be applied to, or used in combination with observations of other physiological signs of the level of fertility in a female, of which she is aware, or can readily be made aware of, e.g. markers in other body fluids.
It is desirable, although not essential, to determine the exact ovulation date in the current cycle. Ovulation day can be determined by any of the known chemical or physiological parameters, although a preferred method is by measuring the level of LH. Once the LH surge previously referred to has been detected, it can be said that ovulation of the user is imminent. Also, the day of the cycle on which ovulation has occurred can be noted for future reference. If the LH surge is detected, and hence the day of ovulation accurately pinpointed, it can be indicated to the user with a very high degree of certainty that the user will no longer be fertile four days hence (3 days after ovulation). For practical purposes, a urinary LH concentration of 20 mIU/ml can be regarded as a universal threshold indicative of the LH surge under virtually all circumstances.
Another method for predicting the end of the fertile period (though not so accurately the day of ovulation) is to measure the levels of the urinary hormone P3G. P3G has a relatively low level in urine until the start of the luteal phase, at which point its level rises fairly sharply. Therefore, once an elevated level of P3G is detected, it can be indicated to the user that the luteal phase of the cyclexe2x80x94ie. the terminal infertile periodxe2x80x94has commenced. An elevated level of urinary P3G can be based on data taken during the current and/or one or more preceding cycles. An xe2x80x9celevatedxe2x80x9d P3G level can be recorded, for example, when either the level of P3G detected is greater than the sum of the four previous recorded levels of P3G in the same menstrual cycle, or greater than 3500 ng/mI, whichever of these two thresholds is lower and is first achieved. Once an xe2x80x9celevatedxe2x80x9d P3G level is recorded, the user can be that she is infertile for the remainder of that cycle.
In a preferred embodiment, the detection of either LH or P3G can be used as a trigger to indicate to the user that the user is no longer fertile until the end of the cycle, with one hormone acting as a xe2x80x9cback upxe2x80x9d to the other. However, it is preferred that the detection of LH be used as a primary indicator of whether ovulation has or is about to occur, since the detection of LH lends itself to more accurate determination of the exact ovulation day than the use of P3G.
The method of the invention has the advantage that it allows, with a high degree of accuracy, the determination of an ovulation day, and hence a fertile period, within a cycle. When needed for contraception purposes, this leads to a method of prediction of the fertile period which requires a minimal period of abstinence from unprotected intercourse within any given menstrual cycle.
The method also has the advantage in that it may require less testing within a given month, and hence reduced expense and inconvenience to the user, without any prejudice to the reliability. Detection of an LH peak is not essential, although the detection of the LH peak can be used as a xe2x80x9cback upxe2x80x9d warning of possible fertility in the event that no elevated E3G level is observed.
The method of the invention also has the advantage in that it is independent of the need to input body basal temperature data, hence avoiding a timeconsuming, inconvenient and arguable unreliable procedure for the user to carry out.
The invention also provides a device for monitoring the ovulation cycle of a female mammal comprising means for initiating the recording of a cycle, means for measuring (if necessary in conjunction with one or more testing devices readable by the monitoring device) and recording urinary E3G concentration, means for determining a threshold E3G concentration from measurements taken during the infertile and transition phases of at least one preceding cycle, and means for alerting a user if a measured E3G concentration during the transition phase of a current cycle exceeds the determined threshold.
The initiating means can for example, be an input means such as a switch or button which the user can actuate at the commencement or termination of menses.
Preferably, the monitoring device of the invention also incorporates means for determining actual ovulation, for example by incorporating means to measure and record LH surge or a rise in urinary P3G concentration.
Information can be conveyed to the user by means of a liquid crystal or LED display, for example. If desired, information on the state of fertility can be conveyed by a simple visual indication, eg a combination of colours showing, for example, green for infertile, red for fertile, and yellow for any intermediate stage when conception is less likely but still possible. Conveniently, the red and yellow signals on the device may be combined, such that the device indicates xe2x80x9credxe2x80x9d signal to the user whenever conception is possible. Especially if the device is intended primarily as an aid to contraception, it should xe2x80x9cfail safexe2x80x9d by showing a xe2x80x9cfertilexe2x80x9d signal.
The monitoring device should be programmed to modify (if necessary) its prediction of appropriate threshold for the present cycle, or for a future cycle, on the basis of actual measurements recorded during one or more previous cycles.
The invention further provides a kit for monitoring the ovulation cycle of a female mammal, comprising a monitoring device as set forth above, together with at least one testing device capable of being used to measure the level of one or more urine components. It is envisaged that the monitoring device will generally be of a relatively durable nature and capable of being used over a considerable number of cycles. The testing devices for measuring the urine components are preferably disposable after individual use, and it is therefore envisaged that the user of the monitoring device will need to replenish the testing devices.
An embodiment of the invention is a plurality of disposable body fluid (eg urine) testing devices, packaged with instructions for use in a method according to the invention. These testing devices, where appropriate, can be urine testing devices from each of which the urinary concentrations of E3G and LH can be detremined (where necessary, in conjunction with a monitor device or electronic means as set forth herein).
Methods of detecting body fluid analytes, such as urinary hormone metabolites, suitable for the purposes of this method, are well known to those skilled in the art. In a preferred embodiment, the analyte is detected by assay methods and devices as described in our UK patent GB 2204398, the contents of which are incorporated herein by reference.
Where the method of the invention relies on measurement of a urine component, this must be done on a urine sample. A variety of immunoassay techniques are available which enable urine components to be measured. A wide variety of solid phase testing devices such as dipsticks and chromatographic strips have been described in the literature, and can readily be adapted for use in determining urinary analytes. The device should at least be capable of indicating relative levels of analyte, eg. E3G, in threshold bands. Examples of simple assay technology that can readily be adapted for use in the home is described, for example, in EP 0225054, EP 0183442, EP 0186799, GB 2204398 and EP 383619, the disclosures of these publications being incorporated herein by reference. Disposable assay strips such as those described in GB 2204398 and EP 383619 which simply require to be contacted with urine and which provide an assay result in semi-qualitative form, eg. by means of a series of test zones on the strip which are progressively positive at higher urinary analyte levels, can be used. Multiple strips that respond at different analyte thresholds can be used, rather than a single strip. Alternatively, a visually readable quantitative assay can be based on progression of a visible, eg. coloured, region or xe2x80x9cfrontxe2x80x9d over a surface (eg. radial diffusion), using for example an enzyme-labelled assay.
In a more sophisticated version of an apparatus according to the invention, the recording device can incorporate means for reading the result of the urine assay, eg. by measuring the reflectance or fluorescence from an assay strip. This may enable a more precise numerical indication to be given of the analyte level, and further enhance the accuracy of the method.
In an embodiment of the invention in which two or more analytes are measured simultaneously, such measurement can if desired be performed using a single body fluid testing device, eg. a device incorporating multiple assay strips, or a single strip capable of independently detecting the level of the different analytes.
The detailed electronics of a recording device capable of assimilating, remembering and handling analyte concentration data, as well as providing the preferred electronic features of the device discussed herein, and predicting future cycles on the basis of such data, can readily be provided by those skilled in the electronics art once they have been advised of the factors that such a device must take into consideration, and the information that the device must provide for the user. Such detailed electronics do not form part of the invention. However, by way of example only, the basic functions that may be required in such a device are outlined in FIG. 3 of the accompanying drawings and described briefly below.
If the device for measuring the levels of hormones in the test sample is electronic, conveniently it contains a facility which automatically varies the threshold level of E3G for a particular user, for example from 30 ng/ml to 20 ng/ml or 40 ng/ml if the observed abstinence period for a particular user is undesirably long or short.